Blepharospasm

Joseph Jankovic, M.D.
Professor of Neurology,
Director of Parkinson's Disease Center
and Movement Disorders Clinic,
Department of Neurology, Baylor College of Medicine,
Houston, Texas
http://www.jankovic.org/

Adopted from Neurology Medlink, La Jolla, CA: Arbor Publishing, 2002 (http://www.medlink.com/).

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Etiology
Biologic Basis
Epidemiology
Prevention
Differential diagnosis
Diagnostic workup
Prognosis and complications
Management
References cited
Abbreviations
ICD-10NA code
Synonyms
Variants
Associated disorders
Major keyword descriptors
Minor keyword descriptors
Table 1. Etiology of blepharospasm

Historical note and nomenclature

Involuntary facial movements have been recognized for long time and were depicted by artists who were fascinated how these movements distorted the facial expression. For example, in the 16th century, the Flemish artist Brueghel painted a woman with apparent blepharospasm and involuntary jaw opening. [Jankovic, 1988]. Although the eponym "Meige's syndrome" has been sometimes used to designate idiopathic cranial-cervical dystonia, this term is not appropriate because Talkow in Germany and Wood in the United States described blepharospasm and orofacial dystonia several decades before the 1910 publication by the French neurologist's report. It was not until the 1970's that blepharospasm was recognized as a form of focal dystonia.

Clinical manifestations

Before the development of sustained closure of the eyelids, about a third of the patients report increased frequency of blinking, suggesting that blepharospasm may be due to impairment of mechanisms associated with normal blinking. A recent study showed that blinking in normal individuals is influenced by various behavioral tasks; the blink rate decreases by 74% during reading and increases by 100% during conversation [Bentivoglio et al, 1997]. The increased blinking that precedes blepharospasm is commonly associated with a feeling of irritation in the eyes. It is usually progresses to clonic and later tonic (sustained) contractions of the orbicularis oculi leading to forceful closure of eyelids, often associated with involvement of the corrugator and procerus muscles and compensatory contractions of the frontalis muscles. Up to 20% of patients have unilateral involvement at the onset but the opposite eye becomes involved later in all patients. Blepharospasm is seldom an isolated condition. This form of dystonia is often associated with dystonia in other facial, cervical, perioral, and mandibular muscles (oromandibular dystonia) [Sankhla et al, 1999]. In addition, patients with blepharospasm may have dystonia in the limbs, trunk and vocal cords (spasmodic dysphonia). One study identified several risk factors for spread of blepharospasm: previous head of face trauma with loss of consciousness, age at onset of blepharospasm, and female gender [Defazio et al, 1999].

Blepharospasm may vary from only a slightly annoying condition to a disabling disorder which interferes with daily activities such as reading, watching television, and driving. Up to two thirds of patients are rendered functionally blind by their blepharospasm. Blepharospasm is usually exacerbated by bright light and, as a result, many patients wear sunglasses both outside and inside. The spasms may be transiently alleviated by pulling on an upper eyelid or an eyebrow, pinching the neck, talking, humming, yawning, singing, sleeping, relaxation, reading, concentration, looking down and other maneuvers or sensory tricks ("geste antagonistique") [Jankovic and Fahn, 1998; Gomez-Wong et al, 1998a, Gomez-Wong et al, 1998b]. Unlike idiopathic blepharospasm, which is most prominent when the patient is active, secondary blepharospasm often persists during rest. This distinction, however, is not reliable enough to differentiate primary from secondary blepharospasm.

Psychiatric symptoms, such as anxiety, depression, psychosis, may be present even before or at onset of blepharospasm and was identified in 18% of 264 patients [Grandas et al 1988]. The prevalence of obsessive.compulsive symptoms, often attributed to basal ganglia dysfucntion, in patients with blepharospasm was significantly higher than in those with hemifacial spasm, despite the clinical similarities [Broocks et al, 1998]. This coexistence with mild psychiatric symptoms may explain the tendency to label blepharospasm as a psychogenic problem. However, psychogenic forms of blepharospasm are extraordinarily rare, and there is usually little or no evidence of any a psychopathology in patients with blepharospasm [Scheidt et al, 1996]. In one survey, the diagnosis of blepharospasm was delayed 4 to 10 years in more than half of the patients [Jankovic and Orman, 1984]. Although the latency between the onset of symptoms and the diagnosis is shortening, largely as a result of intensive education of physicians and the public, there are still unacceptably long delays in making the diagnosis.

Clinical Vignette

This 63 year old woman first noted increased blinking and eye irritation at age 60 while walking outside on a sunny, but windy, day. She initially consulted an ophthalmologist and was diagnosed with “dry eyes”. Eye drops and lubricants, however, provided no benefit and she began to notice involuntary closure of her eyes which interfered with her ability to drive, read and watch TV. Within 2 years after the onset of her eye symptoms she began to notice that in addition to her involuntary eyelid spasms, she had involuntary contractions of her paranasal muscles causing an embarrassing facial grimacing. The involuntary facial movements progressed to spasms of the jaws with marked trismus and bruxism resulting in severe jaw pain, diagnosed as temporomandibular joint syndrome by her dentist. She was subsequently evaluated by a neurologist who confirmed the diagnosis of cranial dystonia, manifested chiefly by blepharospasm and jaw-closing oromandibular dystonia. Diazepam, trihexyphenidyl and baclofen provided only minimal benefit, but botulinum toxin (BTX) injections into her eyelids, eyebrows, paranasal muscles and masseter muscles markedly improved her symptoms. She had occasional unilateral ptosis after the treatment, but overall she was pleased with the results of the BTX injections.

Etiology

That blepharospasm represents a forme fruste of idiopathic (primary) torsion dystonia is now well accepted [Jankovic and Fahn, 2002]. In addition to the frequent coexistence of blepharospasm and dystonia in other body segments, the relatively frequent occurrence of family history of dystonia, essential-type tremor, or both supports the hypothesis that blepharospasm and other forms of dystonia may be genetically related. In our experience, one third of all patients with cranial-cervical dystonia has an action hand tremor similar to essential tremor or dystonia, and one third has a first-degree relative with tremor or dystonia [Jankovic and Nutt, 1988]. In the series of Grandas et al [1988] family history of movement disorders was present in 20% of their patients. A study of idiopathic focal dystonias in the United Kingdom confirmed that these movement disorders were genetically transmitted.

The study of blepharospasm due to some specific, identifiable cause (secondary blepharospasm) can provide insights into the pathogenesis of the primary, idiopathic disorder, sometimes referred to as “benign, essential blepharospasm”. While the most common cause of blepharospasm is adult-onset idiopathic torsion dystonia, there are many other, although less common, causes [table 1]. Even though most patients initially consult ophthalmologists, ocular disorders rarely cause blepharospasm [Salorio and Conte, 1988].

Tardive dystonia is probably the most common cause of secondary dystonia, including blepharospasm [Jankovic, 1995; Mauriello et al, 1998]. Tardive dystonia consists of a persistent dystonic movement involving chiefly the face, jaws, neck, trunk, and arms. Blepharospam may be the initial presentation of tardive dystonia [Sachdev, 1998]. In addition to dopamine-receptor blocking drugs (neuroleptics), there are other drugs that can cause blepharospasm, including lithium [Micheli et al, 1999], lamotrigine [Verma et al, 1999], and others [Mauriello et al, 1998].

A variety of CNS lesions involving the rostral brainstem, thalamus, and the basal ganglia, e.g., stroke, multiple sclerosis, thalamotomy, hydrocephalus, have been reported in association with blepharospasm and other forms of cranial dystonia [Jankovic, 1986; Miranda and Millar, 1998; Verghese et al, 1999]. These reports of lesions producing blepharospasm, oromandibular dystonia, or both support the notion that in addition to the basal ganglia, other subcortical and brain stem structures play an important role in the pathophysiology of cranial dystonia.

An animal model of blepharospasm has been proposed. In a rat rendered mildly deficient of dopamine by unilateral injection of 6-hydroxydopamine (6-OHDA) sectioning of the zygomatic branch of the facial nerve contralateral to the 6-OHDA lesion results in blepharospasm [Schicatano et al, 1997]. This is probably due to a reduction in the tonic inhibition of the trigeminal reflex blink circuits as a result of a mild striatal dopamine depletion coupled with an adaptive increase in the drive on the trigeminal sensory-motor blink circuit in response to the facial nerve lesion.

Biologic basis

By definition, the cause of essential (primary, idiopathic) blepharospasm is unknown, but there are several lines of evidence to suggest that genetic factors are important in the pathogenesis of this form of focal dystonia. Several gene loci have been identified for autosomal dominant dystonia, but only one gene mutation has been discovered; a 3 base-pair deletion in a gene coding for a novel ATP-binding protein in the 9q34 locus, termed torsinA, resulting in a loss of a pair of glutamic acid residues [Ozelius et al, 1997]. Although the most common form of genetic dystonia, DYT1 dystonia, is almost never associated with blepharospasm, many patients with familial forms of blepharospasm have been reported [Jankovic and Nutt, 1988]. No gene mutation, however, has been identified. An overexpression of allele 2 with microsatellite repeat in the D5 dopamine receptor gene on chromosome 4 was found in patients with blepharospasm, but it is unlikely that this polymorphism in the DRD5 is functionally related to the pathogenesis of blepharospasm [Misbahuddin et al, 2002]. The authors suggest that a certain haplotype aassociated with allele 2 of the D5 receptor microsatellite confers susceptibility to developing blepharospasm.

Only few patients with cranial dystonia, including blepharospasm, have been studied at autopsy [Gibb et al, 1988; Hallett and Daroff, 1996; Hallett, 2002]. Normal findings or non-specific abnormalities are present in nearly all brains from patients with idiopathic blepharospasm. We reported a 68 year old woman with 7 year history of progressive blepharospasm, spasmodic dysphonia, and cervical dystonia who died in the hospital shortly after the diagnosis of poorly differentiated metastatic adenocarcinoma [Jankovic et al, 1987]. Her brain was collected within 30 minutes and examined histologically as well as biochemically. There were no abnormalities noted on histological examination, but the norepinephrine levels were markedly increased in the brainstem (199.6% in red nucleus and 415.2% in substantia nigra).

Measuring metabolism by using F-18 fluorodeoxyglucose positron emission tomography (PET), Esmaeli-Gutstein et al [1999] showed significantly increased activity in the striatum and thalamus and Hutchinson et al [2000] found increased metabolic activity in the pons and cerebellum. In another study using PET to measure cerebral blood flow before and after vibration applied to the lower face, Feiwell et al [1999] showed that the normal activation of the primary sensorimotor area (PSA) significantly decreased following vibration in patients with blepharospasm. There was also decreased activation of the PSA and supplementary motor area in response hand vibration. This suggests that patients with blepharospasm have abnormal sensorimotor processing, a phenomenon also described in patients with other forms of dystonia. Lack of cortical inhibition rather than abnormal excitation is thought to best explain the excessive movement in patients with dystonia [Hallett, 1995; Hallett, 1998]. In collaboration with the latter group, we used PET to measure the in vivo binding of the dopaminergic radioligand [18F]spiperone in putamen in 21 patients including those with blepharospasm and compared the findings with those from 13 normals. The results indicate a decrease of dopamine D2.like binding in putamen [Perlmutter et al, 1997]. Two patients with atypical cranial dystonia were found to have a mosaic neuronal cell loss and gliosis in the striatum. Neuronal cell loss in the substantia nigra and other brainstem nuclei was reported in 3 patients, 2 of whom had associated Lewy bodies [Mark et al, 1994].

In order to understand the pathoanatomic and pathophysiologic mechanisms of blepharospasm it is important to understand the brainstem pathways controlling lid closure. The trigeminal sensory neurons provide sensory input from cornea and eyelashes to the trigeminal sensory nucleus which extends from the pons to the upper cervical cord. From the caudal trigeminal nucleus there are projections to the ipsilateral oculomotor nucleus and from the rostral trigeminal nucleus there are bilateral projections to both oculomotor nuclei. The midbrain pretectal olivary nucleus controls the size of the pupil in response to the brightness of the light entering the eye and this nucleus may also project to the oculomotor nucleus and cause contraction of the orbicularis oculi. By injecting fluorescent retrograde tracers into selected muscles of the upper and lower face and then injecting anterograde tracers into corresponding regions of the motor cortex of rhesus monkeys, Morecraft et al [2001] defined the musculotopic organization of the facial nucleus. They found that the orbicularis oculi region was innervated chiefly by the rostral cingulate region, called M3. Since this region is usually not affected in typical middle artery stroke, the upper face is usually spared in this type of stroke.

The blink reflex may be elicited by electrical stimulation of the supraorbital nerve and consists of an early, first response (R1) and a late, second (R2) response. Neurophysiologic studies have demonstrated increased amplitude and duration of the R1 and R2 blink response and increased duration of the corneal reflex in patients with blepharospasm and oro-mandibular dystonia has been confirmed by several groups [Berardelli et al, 1985; Grandas et al, 1998]. Lew et al [1992] showed that 87% of patients with cranial-cervical dystonia display increased latency and reduced amplitude of the acoustic reflex in cranial-cervical dystonia. In one study of 17 patients with dystonic blepharospasm and 11 age-matched controls, Gomez-Wong et al [1998a] found that in patients with blepharospasm there was normal prepulse inhibition occurring at 60-100 millisec intervals but the prepulse inhibition for the R2 response was abnormally reduced in 11 (64.7%) patients, including 9 who did not use sensory tricks ("geste antagonistique"). These and other studies support the hypothesis that at least some of the cases of blepharospasm result from hyperexcitability of brainstem interneurons, possibly as a result of dysfunction of descending basal ganglia pathways. Experimental studies in cats and monkeys have found that serotonin (5-HT) facilitates the excitability of facial motoneurons, partly through 5-HT2 receptors which are densely concentrated in the facial nucleus and serotonin agonist produce blepharospasm whereas serotonin antagonists reduce blink frequency [LeDoux et al, 1998]. Furthermore, the normal prepulse inhibition of the trigeminal reflex is abnormal in a percentage of patients with blepharospasm. It is postulated that in these patients the normal sensory gating on trigeminal afferents are disturbed, the normal contact-induced reduction in the gain of trigemino-facial reflexes is lost, and the usual sensory tricks are no longer effective [Gomez-Wong et al, 1998b].

Peripheral trauma is increasingly recognized as a cause of dystonia and peripheral trauma may trigger dystonia in carriers of the idiopathic torsion dystonia gene [Jankovic, 1994; Jankovic 2001]. Up to 12% of patients with blepharospasm report the occurrence of ocular trauma prior to the onset of their movement disorder [Grandas et al, 1988]. Schicatano et al [1997] proposed a two.factor model based on the observation that dopamine depletion reduces the tonic inhibition of trigeminal blink circuit thus creating “a permissive environment within the trigeminal blink circuits” which along with an external ophthalmic insult (second factor), precipitates blepharospasm. They suggest that this two.factor model may also be applicable to the genesis of other dystonias.

Epidemiology

Although considered an unusual or a rare disorder, cranio-cervical dystonia is the most common form of dystonia at Baylor College of Medicine (78% of dystonia patients). The prevalence of blepharospasm is estimated to be 5 per 100,000 [Nutt et al, 1988; Grandas et al, 1988]. In two largest series of patients with blepharospasm, women outnumbered men at a ratio of about 2 to 1 and in two thirds of the patients the movement disorder began after 50 years of age [Jankovic and Orman, 1984; Grandas et al, 1988]. By pooling data from eight European countries, cases diagnosed as blepharospasm by adult neurologists with specialist movement disorder (and BTX) resulted in a prevalence rates for blepharospasm of 36 (95% confidence interval 31-41) per million [The Epidemiological Study of Dystonia in Europe Collaborative Group, 2000]. The authors suggest that because of ascertainment bias, the true prevalence is probably considerably higher. In a study of a region of Southern Italy, Defazio et al [Defazio et al, 2001] found a prevalence of 133 per million and apraxia of eyelid opening was found to co-exist in one third of cases. In their review of published epidemiologic data they concluded that the crude estimated of prevalence range from 16 to 133 per million and that age at onset and female gender are putative risk factors and that prior head and face trauma may increase the risk of spread of dystonia to adjacent body regions [Defazio and Livrea, 2002].

Prevention

Since the majority of cases of blepharospasm are thought to be genetically determined, there is little hope that the disorder will be preventable in the near future. Certainly, the avoidance of dopamine-receptor blocking drugs will prevent the development of tardive blepharospasm.

Differential diagnosis

Idiopathic torsion dystonia accounts for the majority of cases of blepharospasm. Dystonia caused by exposure to dopamine-receptor blocking drugs, tardive dystonia, is probably the second most common cause of blepharospasm. A variety of lesions in the upper midbrain and in the basal ganglia, e.g. stroke, multiple sclerosis, thalamotomy, hydrocephalus, have been reported in association with blepharospasm [Jankovic, 1988; Hallett and Daroff, 1996]. A lesion in the dorsomedial caudal pontine tegmentum also has been associated with blepharospasm [Aramideh et al, 1996]. Cranial-cervical dystonia can also occur in association with diseases of the central nervous system, such as Tourette syndrome, Wilson's disease, Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, postencephalitic parkinsonism, and X-linked dystonia-parkinsonism syndrome. Levodopa replacement in Parkinson's disease can also cause blepharospasm. A few reports have suggested that there may be an association between blepharospasm and autoimmune diseases, specially systemic lupus erythematosus, rheumatoid arthritis, and myasthenia gravis [Nilaver et al, 1990]. Increased blinking can also be a sign of a seizure [Benbadis et al, 1996].

In addition to dystonia, other conditions can lead to closure of the eyelids. Ptosis may result from weakness or paralysis of the levator palpebrae muscle or the smooth muscle of Müller. Some patients are unable to open their eyes because they cannot "activate" the levator palpebrae muscles. This is analogous to the motor blocks or the freezing phenomenon experienced by some and the terms “apraxia of eyelid opening” and "eyelid freezing" are used to describe this disorder. The inability to open eyes has been attributed to absence of contraction or even inhibition of the levator palpebrae (despite compensatory frontalis contraction) [Golbe et al, 1989; Krack and Marion, 1994]. Based on clinical and electrophysiological observations in 6 patients, Elston [1992] argued that this sign was caused by isolated contraction of the pre-tarsal orbicularis oculi. In some cases electromyographic (EMG) recording from the levator palpebrae and orbicularis oculi muscles is required to differentiate this persistent pretarsal orbicularis oculi contraction from the levator inhibition [Aramideh et al, 1995]. EMG has been used to detect an abnormal persistence of orbicularis oculi activity in patients with apraxia of eyelid opening [Tozlovanu et al, 2001]. Progressive supranuclear palsy is the most common cause of eyelid freezing seen in the Parkinson's clinic, but other parkinsonian syndromes, Huntington's disease, hemispheric cerebral vascular disease, and neuroacanthocytosis are occasionally associated with this phenomenon. Apraxia of eyelid opening, however, can occur in isolation without any other motor deficits and it may improve with levodopa [Dewey and Maraganore, 1994].

Involuntary contractions of the orbicularis oculi muscle can be also caused by ophthalmologic disorders, possibly mediated by the trigeminal-palpebral reflex (e.g. blepharitis, conjunctivitis, "dry eye syndrome", keratitis, iritis, uveitis) or the optico-palpebral reflex (e.g. albinism, achromatopsia, maculopathies) [Jankovic, 1988]. Reflex blepharospasm is also seen in premature infants, patients with various parkinsonian syndromes, lesions in the nondominant temporoparietal lobe (Fisher's sign), and in response to loud noise (cochleopalpebral reflex), sudden free fall (vestibulopalpebral reflex), and gag (palatopalpebral reflex). Medial frontal hypometabolism has been demonstrated with [18F] fluorodeoxyglucose positron emission tomography in 4 patients with lid opening apraxia who had no pyramidal or extrapyramidal dysfunction [Smith et al, 1994].

Contraction of orbicularis oculi with eyelid closure can also result from hyperactivity of the peripheral nervous system. Hemifacial spasm, a form of segmental myoclonus, is characterized by involuntary, paroxysmal, tonic or clonic contractions of the muscles innervated by the 7th cranial nerve [Wang and Jankovic, 1998]. In 1688 patients, mostly women, the cause was unknown in 163 and a vascular abnormality, identified in 509 patients, was the most frequent cause [Digre and Corbett, 1988]. In one study magnetic resonance tomographic angiography showed that 64.9% of patients with hemifacial spasm had ipsilateral vascular compression [Adler et al, 1992]. The presumed pathophysiologic mechanism of hemifacial spasm involves the generation of ortho- and antidromic impulses by a damaged area of the facial nerve. The constant antidromic stimulation may result in "kindling", causing neuronal discharge in the facial motor nucleus, leading to hemifacial spasm. Typically, at onset the patients experience occasional twitches in the eyelids but with the progression the spasms the twitches become more constant and involve the lower facial musculature. The clonic and tonic contractions are triggered by action (smiling, talking, eating, blinking). Hemifacial spasm is easily distinguished from blepharospasm caused by dystonia because it is virtually always unilateral, although there are rare exceptions [Tan and Jankovic, 1999]. Furthermore, in contrast to blepharospasm, patients with hemifacial spasm often exhibit paradoxical raising of the eyebrow as the eye closes (the “other” Babinski sign) [Devoize, 2001]. The term "tic convulsif" describes the rare coexistence of trigeminal neuralgia and hemifacial spasm. The phenomenology of aberrant facial regeneration or facial synkinesis is similar to hemifacial spasm, but the onset usually follows facial palsy. Studies in macaque monkeys show that following facial nerve injury, the orbicularis oculi motoneurons innervate the perioral muscles causing co-contraction (synkinesia) of eyelid and perioral muscles [Baker et al, 1994]. Blepharospasm has been also reported after Bell’s palsy [Chuke et al, 1996; Baker et al, 1997]. Hemimasticatory spasm is a rare disorder whose underlying mechanism is similar to hemifacial spasm but the trigeminal rather than the facial nerve is involved [Auger et al, 1992]. The spasms of the masticatory muscles may or may not be associated with hemifacial atrophy. Facial myokymia, a rapid undulation and flickering of the facial muscles from the frontalis to the platysma is thought to be due to an intramedullary lesion close to the facial motor nucleus. Multiple sclerosis is probably the most common cause, but intra-axial tumors and Guillain-Barré syndrome have also been described as associated with this movement disorder. Tetanus is caused by tetanus toxin, a product of Clostridium tetani, and it is characterized by hyperactivity of motor neurons which causes forceful closure of the eyelids. Although rare in the United States, it still remains a major public health problem in underdeveloped areas. Amyloidosis V and Schwartz-Jampel syndrome (autosomal recessive disorder manifested by combination of blepharospasm, blepharophimosis, dwarfism, muscular hypertrophy, generalized muscular stiffness and myotonia) represent additional causes of blepharospasm.

Blepharoclonus refers to rhythmic contractions of the orbicularis oculi closely resembling tremor, present during gentle closure of the eyelids. Although no apparent cause can be identified in many cases, blepharoclonus is occasionally associated with multiple sclerosis, obstructive hydrocephalus, and Arnlod-Chiari malformation [Jacome, 2001a, Jacome 2001b]. Blinking, the most common motor tic present in 70% of patients with Tourette's syndrome, is characterized by bursts of rapid, non-sustained contractions of the orbicularis oculi. On the other hand, dystonic tics of the eyelids, found in 15% of patients, can cause diagnostic difficulties because they are transiently sustained and may resemble blepharospasm.

An important cause of facial movements is Whipple's disease. In addition to gastrointestinal symptoms, patients with Whipple's disease typically exhibit supranuclear ophthalmoparesis and rhythmic contractions of the eyelids, face and mouth in synchrony with convergent eye oscillations. This oculomasticatory myorhythmia is usually associated with contractions of neck, pharyngeal, and proximal and distal musculature.

The phenomenology of blepharospasm is usually same regardless of its cause. The presence of associated findings, however, may suggest a specific etiology. The recognition of stereotypies (repetitive, patterned, seemingly purposeful but purposeless movements), for example, suggests the diagnosis of tardive dystonia, whereas corneal Kayser-Fleischer ring and evidence of hepatic failure indicate Wilson's disease [Svetel et al, 2001].

Diagnostic workup

Except for a careful ophthalmologic evaluation, there is usually no need for any diagnostic studies. Neuroimaging studies are helpful in the evaluation of patients suspected of having secondary blepharospasm, related to acute stroke, multiple sclerosis, or other etiologies. Rarely, tests for collagen-vascular and autoimmune diseases are indicated.

Prognosis and complications

Blepharospasm is a lifelong disorder in most patients. In most series, less than 3% of all patients experienced prolonged spontaneous remission [Grandas et al, 1988; Jankovic and Orman, 1984; Mauriello et al, 1996], but the remission rate may be as high as 10%, mostly within the first 5 years [Castelbuono and Miller, 1998]. In one series of 238 patients who responded to a questionnaire, however, 11.3% were found to be symptom free after less than 5 years of blepharospasm [Castelbuonno and Miller, 1998]. The duration of remission averaged 6.3 years. It is important, however, to note that this was a retrospective study and the only way to obtain reliable data on remission is through a longitudinal study of prospectively followed cohort of patients. Generally patients have progressive worsening of their symptoms during the first 5 years after onset following which the symptoms stabilize. Up to 15% become legally blind. Complications of chronic untreated blepharospasm include "dry eyes", dermatochalasis (abnormal looseness of the eyelid skin due to constant pulling on the eyelids in an effort to keep the eyes open). In well over 80% of patients with blepharospasm, other facial, oromandibular, pharyngeal, laryngeal and cervical muscles become involved and the focal dystonia gradually evolves into segmental (cranial-cervical) dystonia. In addition to the obvious physical disability, the patients often experience uncomfortable "pulling" sensation behind their eyes. The partial blindness, discomfort and social embarrassment caused by the blepharospasm often leads to anxiety and depression; although psychopathology is remarkably rare in patients with blepharospasm [Scheidt et al, 1996].

Management

There are only few controlled therapeutic trials in blepharospasm, but refinements in clinical rating scales should facilitate future studies [Lindeboom et al, 1995]. Using eyelid crutches or goggles has been reported to be helpful in some patients [Hirayama et al, 2000]. Occasionally, biofeedback and other muscle relaxation techniques and stress management may be helpful, particularly for those patients in whom stress exacerbates the symptoms [Tarbox et al, 1985]. Although BTX injections into the eyelids and eyebrows is considered by many as the treatment of choice, some patients with blepharospasm obtain satisfactory relief from medications, particularly clonazepam (1-8 mg/day) or trihexyphenidyl (2-12mg/day). BTX injections provide moderate or marked improvement in over 90% of patients. Pretarsal injections, particularly into the Riolan’s part of the pretarsal orbicularis oculi seems to provide the most benefit [Jankovic, 1996; Kowal, 1997; Mackie, 2000]. The average latency from the time of the injection to the onset of improvement is 2 to 5 days and the average duration is 3 to 4 months. Following BTX treatments, as a result of reduced eyelid and eyebrow spasms, most patients can function normally and they have less difficulties driving, watching TV, or reading. In addition to the observed functional improvement, there is usually a meaningful amelioration of discomfort and, because of less embarrassment, the patients' self-esteem also frequently improves. Although about 10-15% of all treatment sessions are followed by some side effects (ptosis, blurring of vision or diplopia, tearing, and local hematoma), the complications only rarely affect patient's functioning and usually resolve spontaneously in less than 2 weeks. There is no apparent decline in benefit and the frequency of complications actually decreases after repeat BTX treatments [Jankovic and Schwartz, 1993]. Botulinum toxin F may be a useful alternative for those rare patients who develop blocking antibodies to botulinum toxin A, but its usefulness is limited by substantially shorter duration of benefit [Mezaki et al, 1995]. In a double.blind study of 212 consecutive patients with essential blepharospasm, who received one injection of Botox and one injection of Dysport in two separate treatment sessions, using empirical ratio Botox: Dysport of 1:4 (IU), the average dose of Botox per treatment was 45.4 IU ± 13.3 (range 25.85 IU) and of Dysport 182.1 IU ± 55.1 (range 100.340 IU). There was no difference in the duration of the effect (about 8 weeks), but side effects, particularly ptosis, was more frequent with Dysport as compared to Botox (24.1% vs. 17.0%) (P < 0.05). Botulinum treatment not only improves the frequency and intensity of blepharospasm, but also markedly improves quality of life [Tucha et al, 2001]. Apraxia of eyelid opening is more difficult to treat than blepharospasm, but some patients with apraxia of eyelid opening improve with BTX injections, particularly if it is triggered by blepharospasm [Forget et al, 2002].

Patients who fail to obtain satisfactory control of their blepharospasm with BTX may be candidates for surgical treatment. Facial nerve lysis and orbicularis oculi myectomy, once used extensively in the treatment of blepharospasm have been essentially abolished because BTX treatment is usually very effective and postoperative complications, such as ectropion, exposure keratitis, facial droop and postoperative swelling and scarring are common [Anderson et al, 1998; Chapman et al, 1999]. Patients with severe apraxia of eyelid opening may require frontalis suspension combined with blepharoplasty [deGroot et al, 2000]. Besides BTX and surgery, chemomyectomy with muscle necrotizing drugs, such as doxorubicin, has been tried in some patients with blepharospasm and hemifacial spasm. Severe local irritation currently limits the usefulness of this therapy. However, a modification of the procedure using a combination of bupivacaine/hyaluronidase and Doxil (Sequus, Menlo Park, CA), a liposome-encapsulated form of doxorubicin, may be more effective and safer [McLoon and Wirtschafter, 2001]. Finally, since photophobia may be caused by sympathetically maintained pain, a blockade of the superior sympathetic ganglion with local anesthetic has been reported to improve light-induced eyelid spasm and as such may be possibly useful as a therapeutic modality in patients with blepharospasm [McCann et al, 1999]. One report suggested that the administration of a combination of linoleic acid and alpha-linoleic acid, which presumably modifies the composition and function of neuronal membranes, has improved blepharospasm in a catecholamine-depleted rat model [Mostofsky et al, 2000]. This polyunsaturated free fatty acid, however, has not been tested in patients with blepharospasm.

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